Interactive comorbidity between opioid drug abuse and HIV-1 Tat: Chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons

Sylvia Fitting, Ruqiang Xu, Cecilia Bull, Shreya K. Buch, Nazira El-Hage, Avindra Nath, Pamela E. Knapp, Kurt F. Hauser

Research output: Contribution to journalArticle

Abstract

HIV-1 infection predisposes the central nervous system to damage by opportunistic infections and environmental insults. Such maladaptive plasticity may underlie the exaggerated comorbidity seen with HIV-1 infection and opioid abuse. Although morphine and HIV-1 Tat synergize at high concentrations to increase neuronal death in vitro, we questioned whether chronic low Tat exposure in vivo might contribute to the spectrum of neuropathology through sublethal neuronal injury. We used a doxycycline-driven, inducible, HIV-1 Tat transgenic mouse, in which striatal neuron death was previously shown to be absent, to examine effects of differential Tat expression, alone and combined with morphine. Low constitutive Tat expression caused neurodegeneration; higher levels induced by 7 days of doxycycline significantly reduced dendritic spine numbers. Moreover, Tat expression widely disrupted the endogenous opioid system, altering μ and κ, but not δ, opioid receptor and proopiomelanocortin, proenkephalin, and prodynorphin transcript levels in cortex, hippocampus, and striatum. In addition to markedly reducing spine density by itself, morphine amplified the effect of higher levels of Tat on spines, and also potentiated Tat-mediated dendritic pathology, thus contributing to maladaptive neuroplasticity at multiple levels. The dendritic pathology and reductions in spine density suggest that sustained Tat ± morphine exposure underlie key aspects of chronic neurodegenerative changes in neuroAIDS, which may contribute to the exacerbated neurological impairment in HIV patients who abuse opioids.

Original languageEnglish (US)
Pages (from-to)1397-1410
Number of pages14
JournalAmerican Journal of Pathology
Volume177
Issue number3
DOIs
StatePublished - Sep 2010

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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